Biochemical Journal最新文献

{"title":"Arginine promotes the activation of human lung fibroblasts independent of its metabolism.","authors":"Robert B Hamanaka, Kun Woo D Shin, M Volkan Atalay, Rengul Cetin-Atalay, Hardik Shah, Jennifer C Houpy Szafran, Parker S Woods, Angelo Y Meliton, Obada R Shamaa, Yufeng Tian, Takugo Cho, Gökhan M Mutlu","doi":"10.1042/BCJ20253033","DOIUrl":"10.1042/BCJ20253033","url":null,"abstract":"<p><p>Arginine is a conditionally essential amino acid with known roles in protein production, nitric oxide synthesis, biosynthesis of proline and polyamines, and regulation of intracellular signaling pathways. Arginine biosynthesis and catabolism have been linked to transforming growth factor-β (TGF-β)-induced activation of fibroblasts in the context of pulmonary fibrosis; however, a thorough study on the metabolic and signaling roles of arginine in the process of fibroblast activation has not been conducted. Here, we examined the role and regulation of arginine metabolism in lung fibroblasts activated with TGF-β. We found that TGF-β increases the expression of arginine biosynthetic and catabolic enzymes in lung fibroblasts. Surprisingly, using metabolic tracers of arginine and its precursors, we found little evidence of arginine synthesis or catabolism in lung fibroblasts treated with TGF-β. Despite this, arginine remained crucial for TGF-β-induced expression of collagen and α-smooth muscle actin. We found that arginine limitation leads to the activation of general control nonderepressible 2 (GCN2), while inhibiting TGF-β-induced mechanistic target of rapamycin complex 1 activation and collagen protein production. Extracellular citrulline could rescue the effect of arginine deprivation in an argininosuccinate synthase-dependent manner. Our findings suggest that the major role of arginine in lung fibroblasts is for charging of arginyl-tRNAs and promotion of signaling events which are required for fibroblast activation.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple transactivation domains of EZH2 bind to the TAZ2 domain of p300 and stimulate acetyltransferase function of p300.","authors":"Dustin Becht,Soumi Biswas,Chenxi Xu,Hongwen Xuan,Moustafa Khalil,Ling Cai,Catherine Musselman,Xin Liu,El Bachir Affar,Xiaobing Shi,Gang Wang,Tatiana Kutateladze","doi":"10.1042/bcj20253037","DOIUrl":"https://doi.org/10.1042/bcj20253037","url":null,"abstract":"The H3K27me-specific methyltransferase EZH2 is the catalytic subunit of the repressive complex PRC2. EZH2 is typically implicated in transcriptional silencing but can also activate gene expression. Here, we show that EZH2 contains three adjacent transactivation domains (EZH2TAD) that are recognized by the TAZ2 domain of the transcriptional coactivator and acetyltransferase p300 (p300TAZ2). Binding interfaces identified by chemical shift perturbations in NMR experiments, measurements of binding affinities, and analysis of the complex formation by mass photometry demonstrate that each EZH2TAD can be concomitantly bound by a separate p300TAZ2. Interaction of EZH2TADs with p300TAZ2 stimulates H3K18- and H3K27-specific acetyltransferase activity of p300. We show that in 22Rv1 prostate cancer cells EZH2 occupies a large set of gene loci lacking H3K27me3, and these non-canonical genomic sites are instead co-occupied by p300, RNA Pol II and BRD4, and are rich in histone marks associated with transcriptional activation. Our findings shed light on the potential basis for such a high degree genetic co-localization through the direct association of p300TAZ2 with EZH2TADs.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"44 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay of constipation, intestinal barrier dysfunction and fungal exposome in aetiopathogenesis of Parkinson's disease: hypothesis with supportive data.","authors":"Chianna Umamahesan, Aleksandra Pilcicka, Jennifer Yick, Kieran Baker, Melvyn Smith, David Taylor, Yun Ma, Benjamin H Mullish, Julian R Marchesi, Steven Gilbert, Shervin D Sadeghi Nasab, David Moyes, Polychronis Pavlidis, Bu'Hussain Hayee, Sylvia M Dobbs, R John Dobbs, André Charlett","doi":"10.1042/BCJ20240621","DOIUrl":"10.1042/BCJ20240621","url":null,"abstract":"<p><p>Constipation is a forerunner to Parkinson's disease (PD) diagnosis, worsening thereafter. We explore the relationship of intestinal barrier dysfunction to constipation and whether intestinal fungal load is an aggravating factor. Fungal load was quantified by real-time PCR, using ITS1F-ITS2 primer set, on microbial DNA extract from stool in 68 participants with PD, 102 without. Fungal load was 60% higher per decade after age 60 years, with no PD status interaction with age. After age adjustment, it was associated inversely with dietary renal acid load. It was unrelated to the presence of constipation or barrier dysfunction. Neither consumption of antimicrobials nor of other targeted exogenous substances was associated. Enzyme-linked immunosorbent assays measured barrier dysfunction markers, faecal alpha-1 antitrypsin (AAT), zonulin and serum intestinal fatty acid-binding protein (I-FABP). Barrier dysfunction was associated with constipation and slower radiographic colonic transit. Functional constipation was 28% more frequent with a doubling of AAT concentration. More colonic-transit test markers were retained in the transverse colon, the higher the AAT and zonulin concentrations, anatomically spotlighting abnormality for the entire colon. In contrast, the concentration of the small intestinal barrier marker I-FABP was associated with looser stool consistency, which is consistent with secondary microbial overgrowth. By showing a relationship of intestinal barrier dysfunction to constipation, this study supports the hypothesis that dysfunction may be consequential. Dysfunction may be a necessary, but not sufficient, precursor to PD, in allowing inflammaging. Since ageing is the clearest risk for PD, a gut pathogen escalating in abundance from the sixth decade, integral to fungal load, and whose reproduction and virulence is favoured by alkalinity, tallies.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deregulation of LIMD1-VHL-HIF-1α-VEGF pathway is associated with different stages of cervical cancer.","authors":"","doi":"10.1042/BCJ20170649_RET","DOIUrl":"https://doi.org/10.1042/BCJ20170649_RET","url":null,"abstract":"","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"482 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction: Association of P16-RBSP3 inactivation with phosphorylated-RB1 over-expression in basal-parabasal layers of normal-cervix unchanged during CACX development.","authors":"","doi":"10.1042/BCJ20160323_RET","DOIUrl":"https://doi.org/10.1042/BCJ20160323_RET","url":null,"abstract":"","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"482 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisiting nephrin signaling and its specialized effects on the uniquely adaptable podocyte.","authors":"Casey R Williamson, Una V Pantic, Alice Y Wang, Nina Jones","doi":"10.1042/BCJ20230234","DOIUrl":"10.1042/BCJ20230234","url":null,"abstract":"<p><p>Nephrin is a transmembrane Ig-like domain-containing protein that serves as a central structural and signaling scaffold in kidney filtration. First identified in 1998 as mutated in congenital nephrotic syndrome, the recent identification of nephrin autoantibodies in acquired kidney diseases has sparked renewed interest in nephrin biology. In specialized cells known as podocytes, nephrin helps establish and maintain the slit diaphragm (SD), a unique cell-cell junction formed between interdigitating cell projections known as foot processes (FPs). Together, the SD and FP are among the first stages of renal filtration, where they are subject to numerous biochemical and mechanical stressors. Although podocytes are highly adapted to this environment, over time and with injury, this elevated strain can lead to pathological structural changes, detachment, and proteinuria. As such, the complex set of signaling mechanisms provided by nephrin are essential for controlling podocyte adaptability. Herein, we provide a thorough and up-to-date review on nephrin signaling, including a focus on cross-talk between nephrin interactors and signaling regions across podocytes. We first highlight new findings regarding podocyte structure and function, followed by an emphasis on why nephrin is among the most critical proteins for maintaining these features. We then detail a comprehensive list of known nephrin interactors and describe several of their effects, including calcium regulation, cell survival, cell polarity, phase separation-mediated actin reorganization, and SD-focal adhesion dynamics. Collectively, our emerging understanding of the broader cellular context of nephrin signaling provides important insight for clinical strategies to mitigate podocyte injury and kidney disease progression.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"482 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leucine-rich repeat kinase 2 biomarkers for Parkinson's disease.","authors":"Nicolas Dzamko","doi":"10.1042/BCJ20253099","DOIUrl":"10.1042/BCJ20253099","url":null,"abstract":"<p><p>Leucine-rich repeat kinase 2 (LRRK2) has emerged as a promising therapeutic target for the treatment of neurodegenerative Parkinson's disease (PD). Data from a multitude of pre-clinical models are supportive of a potential role for LRRK2 therapies to ameliorate cellular dysfunctions found in PD, and small molecules to inhibit LRRK2 kinase activity, as well as antisense oligonucleotides to target the protein itself, are in clinical trials. Despite this, exactly how LRRK2 contributes to PD pathogenesis remains to be determined, and definitive biomarkers to track LRRK2 function are still required. Such biomarkers can be useful for monitoring the pharmacodynamic response of LRRK2 therapeutics and/or understanding the relationship between LRRK2 and the clinical progression of PD. Moreover, biomarkers that can identify increased LRRK2 levels or activity beyond just carriers of pathogenic LRRK2 mutations will be important for expanding LRRK2 therapeutics to other PD populations. This review summarizes recent findings regarding biomarkers of LRRK2.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"482 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LRRK2-mediated mitochondrial dysfunction in Parkinson's disease.","authors":"Silas A Buck, Laurie H Sanders","doi":"10.1042/BCJ20253062","DOIUrl":"10.1042/BCJ20253062","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor, rigidity, and bradykinesia as well as degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). A minority of PD cases are familial and are caused by a single genetic mutation. One of the most common PD-causing genes is leucine-rich repeat kinase 2 (LRRK2), which causes an autosomal dominant PD that presents very similarly to sporadic PD. Pathogenic mutations in LRRK2 increase its kinase activity, indicated by both LRRK2 autophosphorylation and phosphorylation of its substrates. To date, the mechanism(s) by which elevated LRRK2 kinase activity induces DA neuron degeneration and PD has not been fully elucidated. One potential mechanism may involve the role of LRRK2 on mitochondria, as mitochondrial dysfunction has been linked to PD pathogenesis, and exciting recent evidence has connected PD pathogenic mutations in LRRK2 to multiple aspects of mitochondrial dysfunction associated with the disease. In this review, we discuss the current knowledge implicating LRRK2 in mitochondrial energetics, oxidative stress, genome integrity, fission/fusion, mitophagy, and ion/protein transport in PD, as well as examine the potential role LRRK2 may play in mediating the effects of mitochondrial therapeutics being investigated for treatment of PD.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"482 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular basis and therapeutic implications of binary YAPOn/YAPOff cancer classes.","authors":"Pinky Sharma, Yale S Michaels, Joel D Pearson","doi":"10.1042/BCJ20253077","DOIUrl":"10.1042/BCJ20253077","url":null,"abstract":"<p><p>Cancers have traditionally been classified based on their tissue of origin. However, with advances in sophisticated genome sequencing techniques and progression toward an era of precision medicine, it has become increasingly clear that classifying tumors based on unifying molecular features instead of tissue of origin may hold the key to improving patient outcomes. Various efforts have been undertaken to address this critical aspect of cancer biology, but it is still unclear as to the best approach to stratify tumors into different molecular classes. One approach is to define many small subclasses based on complex molecular signatures, while another option is to divide cancers into larger groups based on higher-order features of cancer behavior. This latter approach holds appeal as it may provide opportunities to identify broadly relevant therapeutics. However, our understanding of these fundamental 'rules' of cancer biology and how they can be used to better classify and treat cancers is in its infancy. We recently demonstrated that cancers can be functionally stratified into binary YAPon and YAPoff super-classes with unique therapeutic vulnerabilities based on distinct expression and function of the transcriptional coactivators, YAP and TAZ. In YAPon cancers, YAP and TAZ drive oncogenesis, whereas in YAPoff cancers, YAP and TAZ are instead tumor suppressors. In this review, we discuss our understanding of these distinct cancer classes with a focus on the mechanisms that underlie the opposite function of YAP/TAZ in YAPon and YAPoff cancers, as well as the potential therapeutic implications of these findings.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"482 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The bacterial transcription terminator, Rho, functions as an RNA:DNA hybrid (RDH) helicase in vivo.","authors":"Ankita Bhosale,Ranjan Sen","doi":"10.1042/bcj20253089","DOIUrl":"https://doi.org/10.1042/bcj20253089","url":null,"abstract":"Ribonuclease HI (rnhA) removes the deleterious RNA:DNA hybrids (RDHs) by cleaving its RNA component. The bacterial transcription terminator Rho is an RNA-dependent 5' → 3' helicase capable of unwinding RDH formed on a single-stranded RNA in vitro. We hypothesize that Rho might be directly involved in RDH removal in vivo. Here, we demonstrate that Rho primary RNA-binding site (PBS) mutants defective in RNA binding and helicase activity are synthetically lethal specifically when RNase HI is absent. This lethality was not observed in the absence of RNase HII (rnhB) alone. Rho-PBS mutants in an rnhA- strain exhibited increased plasmid-concatemer and plasmid copy number, altered cell morphology, and were highly susceptible to DNA-damaging agents. These Rho mutants increased the accumulation of RDHs in vivo, suggesting defects in the RDH removal process. Rho was colocalized to RDHs in vivo when RNase HI was absent. Certain catalytically inactive mutants of RNase H that bind to the RDH blocked the entry of Rho to the RDH, inducing cell death, indicating the role of Rho in the removal of deleterious RDHs in the absence of RNase HI. Under in vitro conditions, Rho was capable of binding to the RDHs and unwinding them in a rut-site-dependent manner. Therefore, we concluded that in the absence of RNase HI, Rho, by its RNA-dependent helicase activity, is capable of unwinding RDHs in a rut-site-dependent manner. These results establish the non-transcription terminator role of Rho and its functional synergy with RNase HI in vivo.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"16 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144146099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}